Colorectal cancer is the second most common cause of cancer-related death in both men and women in the Western hemisphere. According to American. Cancer Society, an estimated 106,680 new cases of colon cancer with 57,460 deaths of both males and females would occur in the U.S. in the year 2006. Prognosis depends on the stage of the tumor at the time of diagnosis, with surgery being the most effective treatment. Colorectal cancers develop through a series of histological distinct stages from “adenoma to carcinoma.” The temporal order in which mutations occur in different genes relates to the progression through the histological stages of cancer from adenoma to carcinoma. Mutations of the adenomatous polyposis coli (APC)*, Ki-ras, deleted in colorectal cancer (DCC), and p53 genes play important roles at different stages of colorectal tumorigenesis. Mutation of the APC gene is an early event in familial adenomatous polyposis (FAP), a syndrome of inherited predisposition to colon cancer. Notably, mutations in the APC gene also are found in 60 to 80% of sporadic colorectal cancers and adenomas.
APC is expressed constitutively within the normal colonic epithelium; however, little is known about how mutations of (or abnormal expression of) APC contribute to the development of colon cancer. The APC gene product is a 310-kDa-homodimeric protein localized in both the cytoplasm and the nucleus. Previous studies indicate that the cellular level of wild-type APC is critical to cytoskeletal integrity, cellular adhesion, and Wingless/Wnt signaling. Wild-type APC binds to EB1 and a tumor suppressor protein, DLG that regulates microtubule polymerization and cell cycle progression from Go/G1 to S phase, respectively. In addition, APC may act as a negative regulator of β-catenin signaling in the transformation of colonic epithelial cells and in melanoma progression. The β-catenin/Tcf4 complex regulates the proto-oncogene and cell cycle regulator c-myc, the G1/S-regulating cyclin D1, the gene encoding the matrix-degrading metalloproteinase, matrysin, the AP-1 transcription factors c-jun and fra-1 and the urokinase-type plasminogen activator receptor gene.
An association has been shown between the severe polyposis phenotype and germline mutations in the mutation cluster region (MCR) of APC. Selective pressure for an MCR mutant has been proposed based on the germline mutation in FAP. Patients with mutations outside of the MCR region have a milder phenotype. The mechanism(s) by which APC mutations may contribute to the accumulation of mutations in other genes that are associated with the colon cancer progression remains unclear.